Abstract
Objective: This study aimed to develop a parent-metabolite joint population pharmacokinetic model to characterize the pharmacokinetic (PK) profile for phosphocreatine (PCr) and its metabolite creatine (Cr) in children with myocarditis and to use this model to study the PK profile of different dosing schemes. Methods: One hundred pediatric patients with myocarditis were enrolled. Blood samples were collected at baseline and approximately 30, 40 or 50, 75, and 180 min after a single dose of phosphocreatine sodium. Plasma PCr and Cr concentrations were determined using an HPLC-MS/MS method. A nonlinear mixed effect model approach was used to build the population pharmacokinetic model. After validation, the model was used for simulations to evaluate the PK profile of different dosing schemes. Results: A total of 997 plasma concentrations (498 for PCr and 499 for Cr) were included in the analysis. A four-compartment chain model (central and peripheral compartments for both PCr and Cr) with the first-order elimination adequately characterized the in vivo process of PCr and Cr. Allometric scaling based on bodyweight was applied to the PK parameters. The covariate analysis identified that the glomerular filtration rate (GFR) was strongly associated with Cr clearance. Bootstrapping and visual predictive checks suggested that a robust and reliable pharmacokinetic model was developed. The simulation results showed that PCr had no accumulation in vivo. With the infusion of PCr, the concentration of Cr increased rapidly. Conclusion: A joint population pharmacokinetic model for PCr and Cr in pediatric patients with myocarditis was successfully developed for the first time.
Highlights
Pediatric myocarditis is a common disease of the cardiovascular system in children (Bejiqi et al, 2019)
Inclusion criteria were 1) age less than 18 years, 2) male or female, 3) clinically diagnosed pediatric myocarditis, and 4) the acute stage in the clinical stage of myocarditis
In the visual predictive check (VPC) plot, the 90% prediction interval (90% PI) is the area between the predicted 5th and 95th percentiles, and the majority of actual observations fell within the 90% PI
Summary
Pediatric myocarditis is a common disease of the cardiovascular system in children (Bejiqi et al, 2019). It has become a serious threat to the life and health of children owing to its complex clinical manifestations, rapid illness development, and lack of specificity diagnosis methods (Niu et al, 2015). Phosphocreatine (PCr) is an important endogenic high-energy phosphate compound in humans and mammals. It has a crucial role in cellular energy metabolism by acting as an immediate temporal. Exogenous complementary PCr is believed to help solve the most fundamental problem of energy metabolism in damaged myocardium, and it has been used as a cardioprotective drug and used in patient therapy after heart failure or myocardial infarction (Sharov et al, 1986; Saks et al, 1992; Korge et al, 1998; Strumia et al, 2012)
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